USPTO Patents Application 10024648

United States Patent and Trademark Office

UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office

Address: COMMISSIONER FOR PATENTS
P.O.Box 1450

Alexandria, Virginia 223 13-1450
www.uspto.gov

APPLICATION NO.

FILING DATE

FIRST NAMED INVENTOR

ATTORNEY DOCKET NO.

CONFIRMATION NO.

10/024,648

12/19/2001

Heather J. Belmont

49663 (71758)

2636

21874 7590 06/16/2004

EDWARDS & ANGELL, LLP
P.O. BOX 55874
BOSTON, MA 02205

EXAMINER

WEHBE, ANNE MARIE SABR1NA

ART UNIT

PAPER NUMBER

1632

DATE MAILED: 06/16/2004

Please find below and/or attached an Office communication concerning this application or proceeding.

PTO-90C (Rev. 10/03)

Application No.

Applicant(s)

10/024,648

BELMONT ET AL.

Office Action Summary

Examiner

Art Unit

Anne Marie S. Wehbe

1632

- The MAILING DATE of this communication appears on the cover sheet with the correspondence address -
Period for Reply

A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE 3 MONTH(S) FROM
THE MAILING DATE OF THIS COMMUNICATION.

- Extensions of time may be available under the provisions of 37 CFR 1 .136(a). In no event, however, may a reply be timely filed
after SIX (6) MONTHS from the mailing date of this communication.

- If the period for reply specified above is less than thirty (30) days, a reply within the statutory minimum of thirty (30) days will be considered timely.

- If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication.

- Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any
earned patent term adjustment. See 37 CFR 1 .704(b).

3) D Since this application is in condition for allowance except for formal matters, prosecution as to the merits is

closed in accordance with the practice under Ex parte Quay/e, 1935 CD. 1 1 , 453 O.G. 213.

Disposition of Claims

4) [3 Claim(s) 1-113 is/are pending in the application.

4a) Of the above claim(s) 9-29, 32-37 and 48-111 is/are withdrawn from consideration.

5) 0 Claim(s) is/are allowed.

6) E3 Claim(s) 1-8,30.31,38-47,112 and 113 is/are rejected.

7) D Claim(s) is/are objected to.

8) D Claim(s) are subject to restriction and/or election requirement.

Application Papers

9) D The specification is objected to by the Examiner.

10)[X] The drawing(s) filed on 14 May 2002 is/are: a)[x] accepted or b)D objected to by the Examiner.

Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1 .85(a).

Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121(d).
1 1 )□ The oath or declaration is objected to by the Examiner. Note the attached Office Action or form PTO-152.

Priority under 35 U.S.C. § 119

12)D Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 1 19(a)-(d) or (f).
a)D All b)D Some * c)D None of:

1 .□ Certified copies of the priority documents have been received.

2.D Certified copies of the priority documents have been received in Application No. .

3-D Copies of the certified copies of the priority documents have been received in this National Stage
application from the International Bureau (PCT Rule 17.2(a)).
* See the attached detailed Office action for a list of the certified copies not received.

Status

1 )S Responsive to communication(s) filed on 29 March 2004 .
2a)D This action is FINAL. 2b)[X] This action is non-final.

Attachment(s)

1) ^ Notice of References Cited (PTO-892)

2) O Notice of Draftsperson's Patent Drawing Review (PTO-948)

3) K Information Disclosure Statement(s) (PTO-1449 or PTO/SB/08)

4) Q Interview Summary (PTO-413)

5) □ Notice of Informal Patent Application (PTO-152)

6) □ Other: .

Paper No(s)/Maii Date.

Paper No(s)/Mail Date

U.S. Patent and Trademark Office
PTOL-326 (Rev. 1-04)

Office Action Summary

Part of Paper No./Mail Date 061004

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DETAILED ACTION

Applicant's response to the restriction requirement received on 3/29/04 has been entered.
Claims 1-1 13 are pending in the instant application. Applicant's election without traverse of the
subject matter of Group I, and further the species of "transgenic mouse" is acknowledged. As a
result of applicant's election, claims 9-29, 32-37, and 48-1 1 1 have been withdrawn from further
consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and species,
there being no allowable generic or linking claim. Election was made without traverse in the
reply filed on 3/29/04. Claims 1-8, 30-31, 38-47, and 112-113 are currently under examination.
An action on the merits follows.

Please note that claims 1-8, 30-31, 38-47, and 1 12-11 have only been examined to the
extent that they read on the elected subject matter.

Claim Objections

Claims 4-8, 30-31, and 42-47 are objected to under 37 CFR 1 .75(c) as being in improper
form because a multiple dependent claim cannot depend from any other multiple dependant
claim. See MPEP § 608.01(n). Accordingly, the claims 4-8, 30-31, and 42-47 have not been
further treated on the merits.

Please note, however, that in the interests of compact prosecution, the subject matter of
the objected claims, claims 4-8, 30-31, and 42-47, have been considered for the purposes of prior

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art and enablement based on the claim limitations as best as they can be interpreted in view of
the improper multiple dependency of these claims.

Claim Rejections - 35 USC § 103

The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all
obviousness rejections set forth in this Office action:

(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in
section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are
such that the subject matter as a whole would have been obvious at the time the invention was made to a person
having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the
manner in which the invention was made.

This application currently names joint inventors. In considering patentability of the
claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various
claims was commonly owned at the time any inventions covered therein were made absent any
evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1 .56 to point out
the inventor and invention dates of each claim that was not commonly owned at the time a later
invention was made in order for the examiner to consider the applicability of 35 U.S.C. 1 03(c)
and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).

Claims 1-7, 30-31, 38-39, 42-47, and 112 are rejected under 35 U.S.C. 103(a) as being
unpatentable over 5,859,312 (1/12/99), hereafter referred to as Littman et al. in view of
Mombaerts et al. (1993) Cell, Vol. 75, 275-282, and McMurry et al. (1997) Mol. Cell Biol.,
Vol. 17 (8), 4553-4561. The applicant claims transgenic mice which have inactivated
endogenous TCR loci, and whose genome contain transgenes composed of human T-cell

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Art Unit: 1632

receptor loci, and methods of making said transgenic mice. The applicant further claims said
mice and methods wherein the inactivated loci are endogenous TCR alpha and beta loci, wherein
the transgenes comprises unrearranged V, D and/or J and C genes, and wherein the endogenous
TCR loci have been inactivated by deleting the endogenous D, J, and or C genes.

Littman et al. teaches general methods for producing transgenic non-human animals,
preferably mice, which express human lymphocyte transduction proteins and lack expression of
the cognate murine lymphocyte transduction protein as a result of inactivation of the endogenous
lymphocyte transduction gene loci (Littman et al., abstract, columns 4-6). Littman et al. further
teaches that the lymphocyte transduction gene loci and lymphocyte transduction genes include
the T cell receptor genes and particularly the T cell receptor alpha and beta gene products
(Littman et al., columns 8-9). Littman et al. further provides substantial guidance for making
transgenic mice which comprise a human lymphocyte transduction transgenes in their genome
and which have inactivated cognate lymphocyte transduction transgenes (Littman et al., columns
14-36).

Littman et al. differs from the instant invention by not specifically describing a transgenic
mouse in which the TCR loci are inactivated and human rearranged or unrearranged TCR V, D
and/or J, and C genes have been inserted into the genome. It is noted that although Littman et al.
suggests and provides motivation for inactivating the TCR loci of mice and inserting human
TCR loci, Littman et al. exemplifies CD4 loci, not TCR loci. However, at the time of filing,
transgenic mice which expressed unrearranged human T cell receptor loci and mice with have
deletions in the endogenous TCR loci were described and available. Mombaerts et al. for
instance teaches 3 different strains of mice which have inactivating deletions in the TCR alpha

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loci, TCR beta loci, or TCR delta loci (Mombaerts et al, page 275). Mombaerts et al. also
teaches double knock-out mice produced by crossing TCR beta and TCR delta knock-out mice
(Mombaerts et al., page 275). McMurry et al. on the other hand teaches transgenic mice carrying
the human TCR delta gene minilocus. McMurry et al. teaches that the human TCR delta gene
minilocus comprises unrearranged human V, D, J, and C gene segments (McMurry et al., page
4553-4554). McMurry et al. teaches that these mice are capable of functionally rearranging the
human TCR delta gene locus. Therefore, based on teaching of Littman et al. for making
transgenic mice which contain a human lymphocyte transduction loci, such as the TCR loci, and
in which the endogenous lymphocyte transduction loci is inactivated, it would have been prima
facie obvious to the skilled artisan to breed the transgenic mice taught by McMurry with any of
the TCR loci knock-out mice taught by Mombaerts et al. in order to produce a transgenic mouse
in which the endogenous TCR alpha, and/or beta, and/or delta loci are inactivated and which
contain the unrearranged human TCR delta loci. Further, based on the substantial direction
provided by all of Littman et al., Mombaerts et al., and McMurry for making transgenic and
knock-out mice, and the high level of skill in breeding and crossing mice, the skilled artisan
would have had a reasonable expectation of success in making a transgenic mouse comprising an
inactivated endogenous TCR loci and comprising a human TCR loci according to Littman et al.
in view of Mombaerts et al.,and McMurry et al..

Claims 1-2, 5, 7-8, 30-31, 38-45 are rejected under 35 U.S.C. 103(a) as being
unpatentable over 5,859,312 (1/12/99), hereafter referred to as Littman et al. in view of
Mombaerts et al (1993) Cell, Vol. 75, 275-282, and Madsen et al. (1999) Nat. Genetics, Vol.

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23, 343-347. The applicant claims transgenic mice which have inactivated endogenous TCR loci,
and whose genome contain transgenes composed of human T-cell receptor loci, and methods of
making said transgenic mice. The applicant further claims said mice and methods wherein the
inactivated loci are endogenous TCR alpha and beta loci, wherein the transgenes comprises
human TCR alpha and beta transgenes, and wherein the endogenous TCR loci have been
inactivated by deleting the endogenous D, J, and or C genes.

Littman et al teaches general methods for producing transgenic non-human animals,
preferably mice, which express human lymphocyte transduction proteins and lack expression of
the cognate murine lymphocyte transduction protein as a result of inactivation of the endogenous
lymphocyte transduction gene loci (Littman et al., abstract, columns 4-6). Littman et al. further
teaches that the lymphocyte transduction gene loci and lymphocyte transduction genes include
the T cell receptor genes and particularly the T cell receptor alpha and beta gene products
(Littman et al, columns 8-9). Littman et al. further provides substantial guidance for making
transgenic mice which comprise a human lymphocyte transduction transgenes in their genome
and which have inactivated cognate lymphocyte transduction transgenes (Littman et al., columns
14-36).

Littman et al. differs from the instant invention by not specifically describing a transgenic
mouse in which the TCR loci are inactivated and human rearranged or unrearranged TCR V, D
and/or J, and C genes have been inserted into the genome. It is noted that although Littman et al.
suggests and provides motivation for inactivating the TCR loci of mice and inserting human
TCR loci, Littman et al. exemplifies CD4 loci, not TCR loci. However, at the time of filing,
transgenic mice which expressed unrearranged human T cell receptor loci and mice with have

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Art Unit: 1632

deletions in the endogenous TCR loci were described and available. Mombaerts et al. for
instance teaches 3 different strains of mice which have inactivating deletions in the TCR alpha
loci, TCR beta loci, or TCR delta loci (Mombaerts et al., page 275). Mombaerts et al. also
teaches making double TCR knock-out mice produced by crossing for instance TCR beta and
TCR delta knock-out mice (Mombaerts et al., page 275). Madsen et al. further supplements the
teachings of Littman et al. and Mombaerts et al. by teaching transgenic mice which comprise
transgenes for the human TCR alpha and beta chains (Madsen et al., page 346). Madsen et al.
further teaches that these mice express functional human TCR on mature T cells and respond to
antigen (Madsen et al., page 343). It is also noted that Madsen et al. teaches crossing these
transgenic mice with mice incapable of immunoglobulin or TCR rearrangement due to disruption
of the RAG2 gene (Madsen et al, page 343). Therefore, based on teaching of Littman et al. for
making transgenic mice which contain a human lymphocyte transduction loci, such as the TCR
loci, and in which the endogenous lymphocyte transduction loci is inactivated, and the additional
motivation provided by Madsen et al. for expressing human TCR transgenes in mice in which the
endogenous TCR loci cannot rearrange, it would have been prima facie obvious to the skilled
artisan to breed the transgenic mice expressing human TCR taught by Madsen et al. with any of
the TCR loci knock-out mice taught by Mombaerts et al. in order to produce a transgenic mouse
in which the endogenous TCR alpha, and/or beta, and/or delta loci are inactivated and which
contain the unrearranged human TCR delta loci. Most particularly, since the transgenes of
Madsen comprise the TCR alpha and beta genes, the motivation for inactivating the cognate loci
in the mouse provided by Littman et al. would have made it prima facie obvious to the skilled
artisan to specifically cross the mice of Madsen et al. with the mice which have inactivated

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endogenous TCR alpha and beta loci. Further, based on the substantial direction provided by all
of Littman et al., Mombaerts et al., and Madsen et al. for making transgenic and knock-out mice,
and the high level of skill in breeding and crossing mice, the skilled artisan would have had a
reasonable expectation of success in making a transgenic mouse comprising an inactivated
endogenous TCR loci and comprising a human TCR loci according to Littman et al. in view of
Mombaerts et al.,and Madsen et al..

Claim Rejections - 35 USC § 112

The following is a quotation of the first paragraph of 35 U.S. C. 112:

The specification shall contain a written description of the invention, and of the manner and process of making
and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it
pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode
contemplated by the inventor of carrying out his invention.

Claims 1-8, 30-31, 38-47, and 112-113 are rejected under 35 U.S.C. 112, first paragraph,
as failing to comply with the enablement requirement. The claim(s) contains subject matter
which was not described in the specification in such a way as to enable one skilled in the art to
which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The applicant claims transgenic mice which have inactivated endogenous TCR loci, and whose
genome contain transgenes composed of human T-cell receptor loci, and methods of making said
transgenic mice. The applicant further claims said mice and methods wherein the inactivated loci
are endogenous TCR alpha and beta loci, wherein the transgenes comprises unrearranged V, D
and/or J and C genes, and wherein the endogenous TCR loci have been inactivated by deleting
the endogenous D, J, and or C genes. It is noted that the broadest claims read on the inactivation

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of any TCR loci including the TCR delta or gamma loci, and that the human transgenes read on

both rearranged and unrearranged human TCR loci.

The specification provides a prophetic description of how to inactivate the murine TCR

alpha or murine TCR beta genomic locus using targeted homologous recombination. The

specification further provides a prophetic description of how to make transgenic mice comprising

portions of the unrearranged human TCR alpha or beta loci. The specification is silent regarding

the TCR delta and gamma loci and fails to provide any description of targeting vectors for

inactivating the endogenous murine TCR delta or gamma loci, or of transgenes, cosmids, or

YACs comprising any portion of the human unrearranged or rearranged TCR delta or gamma

loci. Regarding the human TCR alpha or beta loci, while the specification describes the

unrearranged genomic loci of human TCR alpha and beta, it is silent in regards to any rearranged

human TCR alpha or beta locus or methods of isolating and manipulating such rearranged loci.

The applicant is reminded that 35 U.S.C. 1 12 requires that the specification must teach those of

skill in the art how to make and how to use the invention as broadly claimed. In re Goodman, 29

USPQ2d at 2013 (Fed. Cir. 1994), citing In re Vaeck, 20 USPQ2d at 1445 (Fed. Cir. 1991).

Furthermore, the Federal Circuit has stated that:

a specification need not disclose what is well known in the art. See, e.g.,
Hybritech Inc. v. Monoclonal Antibodies, Inc^ 802 F.2d 1367, 1385, 231 USPQ
81, 94 (Fed. Cir. 1986). However, that general, oft-repeated statement is merely a
rule of supplementation, not a substitute for a basic enabling disclosure. It means
that the omission of minor details does not cause a specification to fail to meet the
enablement requirement. However, when there is no disclosure of any specific
starting material or of any of the conditions under which a process can be carried
out, undue experimentation is required; there is a failure to meet the enablement
requirement that cannot be rectified by asserting that all the disclosure related to
the process is within the skill of the art. It is the specification, not the knowledge

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of one skilled in the art, that must supply the novel aspects of an invention in
order to constitute adequate enablement.

Genentech Inc. v. Novo Nor disk A/S, 42 USPQ2d 1005 (CAFC 1997)

Finally, it is noted that "case law requires that the disclosure of an application shall inform those
skilled in the art how to use applicant's alleged discovery, not to find out how to use it for
themselves." In re Gardner 166 USPQ 138 (CCPA) 1970. By failing to provide any description
for murine or human TCR delta or gamma loci, or for rearranged human TCR alpha or beta loci,
or for any of the materials such as cosmids, primers, or vectors, necessary to isolate and
manipulate such DNA sequences, the specification fails to provide an enabling disclosure for
making transgenic mice with any inactivated endogenous TCR loci, or for making transgenic
mice with any inserted human TCR loci. Thus, based on the lack of description provided by the
specification as discussed above and the breadth of the claims, it would have required undue
experimentation for the skilled artisan to make transgenic mice according to the instant invention
in which the murine or human TCR loci are TCR delta or gamma loci, or wherein the human
TCR loci is a rearranged human TCR alpha and/or beta loci.

The specification further fails to provide an enabling disclosure for transgenic mice
which comprise unrearranged human TCR alpha or beta loci comprising a plurality of V, D
and/or J, and C genes, and wherein the mice are capable of productively rearranging the human
loci and producing mature T cells which express human TCR on the cell surface and respond to
antigen. The specification teaches that the purpose for making the transgenic mice of the instant
invention is for the production of human TCRs that are reactive with human antigens and thus
can be used as therapeutic agents in human patients. As noted above, while the specification

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provides a prophetic description for making a transgenic mouse with inactivated endogenous
TCR alpha and beta loci and which comprises human unrearranged TCR alpha and beta loci, the
specification provides not actual data for any mouse made according to the disclosed methods.
At the time of filing, Madsen et al teaches that even functional rearranged human TCR are
difficult to express in mouse cells (Madsen et al 5 supra, page 343), Kouskoff et al. also states
that at the time of filing, the construction and expression of TCR in mice was an "unwieldy
endeavor" because of the size of the TCR genomic fragments and the lack of evidence as to
which flanking sequences are required for proper expression (Kouskoff et al., 1995) J. Immunol.
Methods, Vol. 180, 273-280, see page 274-275). Kouskoff et al. further teaches that the use of
heterologous promoters to drive expression can lead to abnormal timing and regulation of TCR
gene expression (Kouskoff et al., page 275). Thus, at the time of filing, it is clear that even the
expression of rearranged heterologous TCR in mice was considered difficult and unpredictable.
The expression of functional TCR from unrearranged genomic DNA adds an extra level of
complexity to the equation and thus increases the unpredictability of achieving successful
functional TCR expression on mature T cells in the periphery. Based on the level of difficulty in
expressing heterologous and particularly human TCR in murine cells, the lack of any evidence in
the specification that a mouse made using the described vectors would in fact be capable of
rearranging and expressing functional TCR on the cell surface capable of passing both positive
and negative selection, and the breadth of the claims, it would have required undue
experimentation for the skilled artisan to make the instant invention as claimed.

Further, T cell maturation involves not only the rearrangement of the TCR genes in the
developing T cell, but also successful completion of T cell negative and positive selection in the

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thymus. In particular, failure to achieve positive selection results in T cell death. Selection in the
thymus is mediated by cell-cell contact of the immature T cell with resident thymocytes. Cell-
cell contact is mediated by the interaction of cell surface TCR on the immature T cells with
peptide/MHC and CD4 or CD8 on the thymocytes. In the absence of human MHC molecules and
human CD4 or CD8 on the thymocytes, it is unclear whether the immature T cells expressing
human TCR would successfully pass positive and negative selection. Further, were any T cells to
reach the periphery, these T cells would have been selected based on binding to murine MHC
and CD4 or CD8. Thus, the "human" TCR on any such peripheral murine T cells would be
unlikely to recognize or bind to human peptide MHC complexes. As a result, such "human" TCR
would be no more useful as therapeutics in humans than murine TCR. Thus, in view of the high
degree of unpredictability in achieving successful expression of functional heterologous TCR in
mice, the complexity of T cell maturation, and importance of TCR/MHC interaction during
positive and negative selection in the thymus, the skilled artisan would not have been able to
predict without undue experimentation whether any mature T cells would be produced in a
transgenic mouse according to the instant invention as claimed.

No claims are allowed.

Any inquiry concerning this communication from the examiner should be directed to
Anne Marie S. Wehbe, Ph.D., whose telephone number is (571) 272-0737. The examiner can be
reached Monday- Friday from 10:30-7:00 EST. If the examiner is not available, the examiner's
supervisor, Amy Nelson, can be reached at (571) 272-0804. For all official communications, the

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technology center fax number is (703) 872-9306. For informal, non-official communications
only, the examiner's direct fax number is (571) 273-0737.

Dr. A.M.S. Wehbe

ANNEM.WEHBE'PH.D
PRIMARY EXAMINER